This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A prophylactic HIV-1 vaccine should elicit broadly cross-reactive neutralizing activity. The gp120-gp41 Env protein on the native virion is the primary target for eliciting neutralizing antibodies. Although several features of Env make it difficult to elicit broadly neutralizing antibodies, progress has been achieved in recent years in enhancing the immunity of Env by modifying its structure, employing novel delivery platforms, and co-administration of adjuvants. The use of virus-like particles (VLPs) has shown great potential as a new vaccine platform. Recent studies have also demonstrated that lower titers of neutralizing antibody can protect against low-dose repeated mucosal SHIV challenge in macaques, which mimics infection of humans by sexual contact. Recently we developed novel approaches to produce Env-enriched chimeric HIV VLPs (cVLPs) and found that such cVLPs containing a membrane-anchored form of flagellin or a variable-region truncated flagellin as adjuvants induced high levels of systemic and mucosal HIV specific antibody responses, with broadened neutralizing activity. Our research is testing the hypothesis that the presence of antigen and adjuvant in the same particulate structure will generate an effective HIV vaccine antigen, by delivering both components simultaneously to the same antigen-presenting cells. The combination of Env antigen presentation in its native state combined with a membrane-anchored adjuvant and mucosal delivery provides a promising approach to stimulate strong nAb response against HIV, designed to block the initial step in the infection process.